Toll-like receptors (TLRs) are pattern recognition receptors that bind a variety of microbial products such as microbial membrane lipids or nucleic acids. Antigen presenting cells (APC) including B cells, DCs and macrophages express multiple TLRs that are bound by pathogens to activate NF-κB and MAP kinase pathways, resulting in expression of costimulatory molecules and cytokine secretion. While TLRs are important for defense against infectious disease, increasing evidence suggests that TLRs also function as regulators of immune responses in cancer, autoimmune disease, and transplantation.
CD180 is a toll-like receptor (TLR) with a short cytoplasmic tail, lacking the Toll IL-1 Receptor (TIR) domain that mediates signal transduction and that is shared by all other TLRs. CD180 has an extracellular structure analogous to TLR4, with 22 leucine rich repeats and an associated co-receptor, MD1, required for CD180 expression. CD180 is expressed at relatively high levels by B cells, and at lower levels by dendritic cells (DC) and other myeloid cells.
G28-8 was the first mAb made to CD180, and was found to stimulate proliferation of B cells and to activate rapid calcium mobilization. Antibodies that bind to CD180 in the mouse also cause B cell proliferation and induce MAP kinase activation, and the responses depend upon the expression of the protein tyrosine kinases lyn and btk. However, the mechanism of CD180 signal transduction is unknown since CD180 does not appear to signal directly through its short cytoplasmic tail.
CD180 is thought to be a regulator of TLR-4 responses. In CD180 deficient animals, B cell proliferation and antibody responses to TLR-4 stimulation by LPS were markedly reduced, whereas TNFα production and septic shock after LPS treatment were increased. Thus CD180 has been proposed to be a positive regulator of TLR-4 responses by B cells but a negative regulator of TLR-4 responses by myeloid cells and DCs. There have been no reported studies of the function of engineered CD180 binding domains.